Abstract Pulmonary arterial hypertension (PAH) is characterized by obliterative vascular remodeling in the lungs and progressive increases of pulmonary vascular resistance that cause right heart failure and premature death. Although great strides have been made in treatment of PAH, current therapies fail to reverse the disease and only resulted in a modest improvement in the morbidity and mortality. Employing novel mouse model with Tie2Cre-mediated deletion of Egln1 [encoding hypoxia-inducible factor (HIF) prolyl hydroxylase 2, PHD2] (Egln1Tie2 mice) in endothelial cells (ECs) and hematopoietic cells, we observed severe PAH as evident by markedly elevated right ventricular systolic pressure (RVSP) and severe vascular remodeling including pulmonary vascular occlusion and plexiform-like lesions as seen in patients with idiopathic PAH (IPAH). This unprecedented pulmonary vascular remodeling and hypertensive phenotypes were inhibited in the double mutant mice with genetic deletions of both Egln1 and HIF2?. Our Supporting Data also show that pharmacological inhibition of HIF-2? attenuated the PAH phenotype in Egln1Tie2 mice. Intriguingly, WT bone marrow transplantation resulted in decreased RVSP and RV hypertrophy in Egln1Tie2 chimeric mice, indicating that the bone marrow abnormalities contribute to the severity of PAH in Egln1Tie2 mice. Thus, we hypothesize that PHD2 deficiency in ECs and hematopoietic cells plays a synergistic role in the pathogenesis of obliterative vascular remodeling and severe PAH via activation of HIF-2? signaling in ECs and HIF-1? signaling in hematopoietic cells. The proposed studies will address the following Specific Aims. In Aim 1, we will determine whether severe PAH exhibited in Egln1Tie2 mice recapitulates the pathophysiology of PAH in IPAH patients and define the role of activated HIF-2? signaling secondary to PHD2 deficiency in mediating severe PAH. In Aim 2, we will address the synergistic role of PHD2 deficiency-activated HIF signalings in pulmonary vascular ECs and hematopoietic cells in the mechanisms of severe PAH. Studies in Aim 3 will delineate the molecular basis of severe pulmonary vascular remodeling and resultant PAH seen in Egln1Tie2 mice and explore the translational potential of selectively targeting HIF-2? signaling for the prevention and treatment of PAH in patients. Given the marked similarity of severe PAH seen in Egln1Tie2 mice and in IPAH patients, we expect that the proposed studies have significant translational potential by identifying druggable targets and exploring novel pharmacological agents that can pharmacologically inhibit/reverse vascular remodeling for the prevention and treatment of severe PAH in patients. 1